Cutaneous melanoma is highly lethal and the fifth most common cancer in the U.S. Peak incidence is in middle age adults but the elderly, young adults and even children are affected. Among all cancer types, melanoma is one of the most aggressive in its propensity for extremely early metastasis. Metastatic melanoma is difficult to eradicate and new therapies are urgently needed to limit disease progression. Genetic causes of melanoma align along a continuum of RAS protein signaling whereby BRAFV600E mutation is the most common driver. The mutant BRAFV600E protein depends on MAPK signaling for both initiation and maintenance of tumor growth. Targeting this abnormally-activated pathway with RAF and MEK inhibitors have had limited success in treating this disease due to MAPK signaling reactivation, causing drug resistance. Thus, more mechanistic insights are needed in order to develop combination therapies that can circumvent resistance. We reported that aberrant activation of the small GTPase ARF6, a protein that controls intracellular trafficking, accelerates metastasis of BRAFV600E melanoma. Prior to metastasis, our unpublished data reveal that the protein ARF6 is also required for efficient tumor development and growth in mice with BRAFV600E melanoma. This positions ARF6 as a key regulator at multiple points in disease progression. Indeed, our preliminary data suggest a novel role for ARF6 in MAPK signaling by regulating the nuclear localization of activated, phospho-ERK, a key effector protein for BRAF. Thus, we hypothesize that ARF6 modulates BRAFV600E-mediated tumor progression, controlling MAPK signaling and providing a vulnerable node for pharmacologic inhibition of both tumor growth and metastasis. Using genetic and pharmacologic approaches, including our unique mouse models and a specific ARF6 inhibitor that we helped develop, our goals are to dissect the roles of ARF6 in MAPK signaling, discover new role(s) for ARF6 in tumor cell function, and test the efficacy of ARF6 inhibitors in restricting tumor progression. Pursuant to these goals, we will: 1) Test the hypothesis that ARF6 controls MAPK signaling in BRAFV600E-melanoma; 2) Test the hypothesis that ARF6 is critical for proliferation and survival of BRAFV600E melanoma; 3) Test the hypothesis that pharmacologic inhibition of ARF6 has therapeutic efficacy in BRAFV600E melanoma patient-derived xenografts (MPDX). Successful completion of the aims in this proposal will identify new mechanisms of melanoma progression that are amenable to therapeutic intervention and may position ARF6 as a potential therapeutic target in RAS-mutant cancers.